Lithium is a psychiatrically important agent that is widely used to alleviate the symptoms of affective disorders. The mechanisms of action of this agent in the central nervous system are not well understood. Our preliminary data show that lithium potentiates the modulatory actions of acetylcholine on hippocampal excitatory and inhibitory synaptic transmission. The broad goal of this study is to begin to define mechanisms by which lithium may produce its clinical effects. Using the techniques of electrophysiological recording in the in vitro hippocampal brain slice preparation, we have shown in preliminary results that cholinergic agonists depress both excitatory and inhibitory synaptic transmission. Application of lithium to the hippocampal slices, at clinically relevant concentrations, significantly potentiates these cholinergic effects. We propose to use a variety of electrophysiological recording techniques and pharmacological probes to identify neuronal sites of action of lithium. We believe this will provide significant information toward defining the mechanisms of action of this clinically important agent.